Divergent roles of prostacyclin and PGE2 in human tendinopathy
Abstract Background Tendon disease is a significant global healthcare burden whereby patients experience pain and disability; however, the mechanisms that underlie inflammation and pain are poorly understood. Herein, we investigated the role of prostaglandins as important mediators of inflammation a...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-03-01
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| Series: | Arthritis Research & Therapy |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13075-019-1855-5 |
| _version_ | 1828191614165581824 |
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| author | Filip Bergqvist Andrew J. Carr Kim Wheway Bridget Watkins Udo Oppermann Per-Johan Jakobsson Stephanie G. Dakin |
| author_facet | Filip Bergqvist Andrew J. Carr Kim Wheway Bridget Watkins Udo Oppermann Per-Johan Jakobsson Stephanie G. Dakin |
| author_sort | Filip Bergqvist |
| collection | DOAJ |
| description | Abstract Background Tendon disease is a significant global healthcare burden whereby patients experience pain and disability; however, the mechanisms that underlie inflammation and pain are poorly understood. Herein, we investigated the role of prostaglandins as important mediators of inflammation and pain in tissues and cells derived from patients with tendinopathy. Methods We studied supraspinatus and Achilles tendon biopsies from symptomatic patients with tendinopathy or rupture. Tendon-derived stromal cells (CD45negCD34neg) isolated from tendons were cultured and treated with interleukin-1β (IL-1β) to investigate prostaglandin production. Results Diseased tendon tissues showed increased expression of prostacyclin receptor (IP) and enzymes catalyzing the biosynthesis of prostaglandins, including cyclooxygenase-1 (COX-1), COX-2, prostacyclin synthase (PGIS), and microsomal prostaglandin E synthase-1 (mPGES-1). PGIS co-localized with cells expressing Podoplanin, a marker of stromal fibroblast activation, and the nociceptive neuromodulator NMDAR-1. Treatment with IL-1β induced release of the prostacyclin metabolite 6-keto PGF1α in tendon cells isolated from diseased supraspinatus and Achilles tendons but not in cells from healthy comparator tendons. The same treatment induced profound prostaglandin E2 (PGE2) release in tendon cells derived from patients with supraspinatus tendon tears. Incubation of IL-1β treated diseased tendon cells with selective mPGES-1 inhibitor Compound III, reduced PGE2, and simultaneously increased 6-keto PGF1α production. Conversely, COX blockade with naproxen or NS-398 inhibited both PGE2 and 6-keto PGF1α production. Tendon biopsies from patients in whom symptoms had resolved showed increased PTGIS compared to biopsies from patients with persistent tendinopathy. Conclusions Our results suggest that PGE2 sustains inflammation and pain while prostacyclin may have a protective role in human tendon disease. |
| first_indexed | 2024-04-12T08:41:45Z |
| format | Article |
| id | doaj.art-73d04a215b7f49c39107903d16123640 |
| institution | Directory Open Access Journal |
| issn | 1478-6362 |
| language | English |
| last_indexed | 2024-04-12T08:41:45Z |
| publishDate | 2019-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Arthritis Research & Therapy |
| spelling | doaj.art-73d04a215b7f49c39107903d161236402022-12-22T03:39:51ZengBMCArthritis Research & Therapy1478-63622019-03-0121111210.1186/s13075-019-1855-5Divergent roles of prostacyclin and PGE2 in human tendinopathyFilip Bergqvist0Andrew J. Carr1Kim Wheway2Bridget Watkins3Udo Oppermann4Per-Johan Jakobsson5Stephanie G. Dakin6Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University HospitalNuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic CentreNuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic CentreNuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic CentreNuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic CentreRheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University HospitalNuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic CentreAbstract Background Tendon disease is a significant global healthcare burden whereby patients experience pain and disability; however, the mechanisms that underlie inflammation and pain are poorly understood. Herein, we investigated the role of prostaglandins as important mediators of inflammation and pain in tissues and cells derived from patients with tendinopathy. Methods We studied supraspinatus and Achilles tendon biopsies from symptomatic patients with tendinopathy or rupture. Tendon-derived stromal cells (CD45negCD34neg) isolated from tendons were cultured and treated with interleukin-1β (IL-1β) to investigate prostaglandin production. Results Diseased tendon tissues showed increased expression of prostacyclin receptor (IP) and enzymes catalyzing the biosynthesis of prostaglandins, including cyclooxygenase-1 (COX-1), COX-2, prostacyclin synthase (PGIS), and microsomal prostaglandin E synthase-1 (mPGES-1). PGIS co-localized with cells expressing Podoplanin, a marker of stromal fibroblast activation, and the nociceptive neuromodulator NMDAR-1. Treatment with IL-1β induced release of the prostacyclin metabolite 6-keto PGF1α in tendon cells isolated from diseased supraspinatus and Achilles tendons but not in cells from healthy comparator tendons. The same treatment induced profound prostaglandin E2 (PGE2) release in tendon cells derived from patients with supraspinatus tendon tears. Incubation of IL-1β treated diseased tendon cells with selective mPGES-1 inhibitor Compound III, reduced PGE2, and simultaneously increased 6-keto PGF1α production. Conversely, COX blockade with naproxen or NS-398 inhibited both PGE2 and 6-keto PGF1α production. Tendon biopsies from patients in whom symptoms had resolved showed increased PTGIS compared to biopsies from patients with persistent tendinopathy. Conclusions Our results suggest that PGE2 sustains inflammation and pain while prostacyclin may have a protective role in human tendon disease.http://link.springer.com/article/10.1186/s13075-019-1855-5TendinopathyInflammationPainProstacyclinPGE2 |
| spellingShingle | Filip Bergqvist Andrew J. Carr Kim Wheway Bridget Watkins Udo Oppermann Per-Johan Jakobsson Stephanie G. Dakin Divergent roles of prostacyclin and PGE2 in human tendinopathy Arthritis Research & Therapy Tendinopathy Inflammation Pain Prostacyclin PGE2 |
| title | Divergent roles of prostacyclin and PGE2 in human tendinopathy |
| title_full | Divergent roles of prostacyclin and PGE2 in human tendinopathy |
| title_fullStr | Divergent roles of prostacyclin and PGE2 in human tendinopathy |
| title_full_unstemmed | Divergent roles of prostacyclin and PGE2 in human tendinopathy |
| title_short | Divergent roles of prostacyclin and PGE2 in human tendinopathy |
| title_sort | divergent roles of prostacyclin and pge2 in human tendinopathy |
| topic | Tendinopathy Inflammation Pain Prostacyclin PGE2 |
| url | http://link.springer.com/article/10.1186/s13075-019-1855-5 |
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